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Nuffield Department of Women's & Reproductive Health sits within the Medical Sciences Division of the University of Oxford. The department encompasses multi-disciplinary research across four overarching themes; Cancer, Global Health, Maternal & Fetal Health and Reproductive Medicine & Genetics
Evidence for the effectiveness of immunologic therapies in women with subfertility and/or undergoing assisted reproduction.
Implantation is a critical step in the establishment of a successful pregnancy, depending on a complex immune-endocrine dialogue between the developing embryo and maternal endometrium. Research suggests that altered immunity in the maternal decidua results in implantation impairment and failure. Immunomodulatory drugs have, thus, been widely used in assisted conception to aid embryo implantation, despite an absence of consensus on their effectiveness and safety. We conducted a systematic review and meta-analysis of interventional studies investigating the use of immunomodulators in women undergoing assisted reproduction. Evidence was uncertain of an effect for most of the included interventions, owing to heterogeneous findings and a paucity of high-quality studies. For certain patient subgroups, however, the use of specific immunomodulatory therapies may offer some benefit. There is a need for further large randomized controlled trials to corroborate these findings.
Interventions to prevent miscarriage.
The physical and psychological impact of miscarriage can be devastating. There are many lifestyle and therapeutic interventions that may prevent a miscarriage. In this review, we have outlined the key areas for health optimization to prevent pregnancy loss, drawing on the most up-to-date evidence available. The 3 key areas identified are lifestyle optimization in women, lifestyle optimization in men, and therapeutic interventions. The evidence demonstrates that the treatments to consider are first-trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies.
Genetic causes of sporadic and recurrent miscarriage.
Approximately 80% of miscarriages happen within the first 12 weeks of gestation. More than half of early losses result from genetic defects, usually presenting as abnormal chromosome numbers or gene rearrangements in the embryo. However, the impact of genetics on pregnancy loss goes well beyond embryonic aneuploidy. For example, the use of big data has recently led to the discovery of specific gene mutations that may be implicated in sporadic and recurrent miscarriages. Further, emerging data suggest that genetic factors play a role in conditions for which there is a causative association with recurrent pregnancy loss. Here, we summarize the evidence on the genetics of miscarriage and provide an overview of the diagnosis and prevention of genetic causes associated with sporadic and recurrent pregnancy loss.
Miscarriage syndrome: Linking early pregnancy loss to obstetric and age-related disorders.
Upon embryo implantation, the uterine mucosa - the endometrium - transforms into a robust decidual matrix that accommodates the fetal placenta throughout pregnancy. This transition is driven by the differentiation of endometrial fibroblasts into specialised decidual cells. A synchronised influx of circulating natural killer (NK) cells and bone marrow-derived mesenchymal stem/progenitor cells (BM-MSC) is pivotal for decidual homeostasis and expansion in early pregnancy. We hypothesise that pathological signals interfering with the recruitment or activity of extrauterine cells at the maternal-fetal interface link miscarriage to subsequent adverse pregnancy outcomes, including further pregnancy losses and preterm labour. NK cells and BM-MSC are key homeostatic regulators in multiple tissues, pointing towards a shared aetiology between recurrent miscarriage and age-related disorders, including cardiometabolic disease. We propose the term 'miscarriage syndrome' to capture the health risks associated with miscarriage and discuss how this paradigm can inform clinical practice and accelerate the development of preventative strategies.
Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis.
BACKGROUND: Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored. OBJECTIVES: To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP. SEARCH STRATEGY: We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023. SELECTION CRITERIA: We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications. DATA COLLECTION AND ANALYSIS: We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology. MAIN RESULTS: The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I2 = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I2 = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I2 = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I2 = 0%; low-certainty evidence). CONCLUSIONS: Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia.
Controlled ovarian stimulation protocols for assisted reproduction: a network meta-analysis.
BACKGROUND: Controlled ovarian stimulation (COS) is an essential step in most assisted conception cycles. Different treatment combinations (termed protocols) exist in COS, yet there is no consensus on their relative effectiveness and safety. OBJECTIVES: We aimed to assess the relative effectiveness and safety of COS protocols in clinical practice. SEARCH METHODS: We followed standard Cochrane methodology to conduct extensive electronic searches to 11 June 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing at least two COS protocols using any form of pituitary suppression (gonadotrophin-releasing hormone (GnRH) agonists, antagonists or progestogens) and human menopausal gonadotropin (hMG), urinary or recombinant follicle-stimulating hormone (u/rFSH), with or without luteinising hormone (LH) and/or oral medications (e.g. clomifene or letrozole), for ovarian stimulation. The primary outcomes were the rates of live birth or ongoing pregnancy (LBR or OPR) and ovarian hyperstimulation syndrome (OHSS) per participant after one stimulation cycle. The secondary outcomes were the rates of clinical pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and cycle cancellation per participant, and the number of oocytes, cleavage-stage embryos, blastocyst-stage embryos and cryopreserved embryos per participant. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We conducted pairwise and network meta-analyses (NMA) according to participants' predicted response to COS (normal/unselected, high or low). For each outcome and subgroup of women, we grouped treatment protocols into the following different networks: all pituitary suppression methods; all long GnRH agonist protocols; all short GnRH antagonist protocols; all GnRH agonist flare protocols; all protocols using progestogens for pituitary suppression; and all protocols using ovarian stimulation in the absence of pituitary suppression. Using the Cochrane RoB 1 tool, we restricted our primary analyses to RCTs at low risk of 'selection' and 'other' biases. We presented effect estimates as risk ratios (RR) for dichotomous outcomes, or mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI). We used Review Manager and Stata 18 for the meta-analyses. MAIN RESULTS: We included 338 studies investigating a total of 15 pairwise comparisons between different COS protocols in 59,086 women. Of these, 226 trials included only women with predicted normal response or whose predicted response was unstated, 31 trials included only women with predicted high response and 81 trials included only women with predicted low response. Primary outcome (effectiveness) - LBR or OPR per woman randomised Pituitary suppression methods In women with predicted normal response, short antagonist protocols probably result in little to no difference in LBR or OPR versus long agonist protocols (RR 0.95, 95% CI 0.84 to 1.07; 8 studies, 2817 women; I2 = 0%; moderate-certainty evidence). Network evidence also suggested that ovarian stimulation without pituitary suppression may reduce the LBR or OPR compared with short GnRH antagonist protocols (RR 0.71, 95% CI 0.57 to 0.90; low-certainty evidence) and with GnRH agonist flare protocols (RR 0.52, 95% CI 0.36 to 0.75; low-certainty evidence). Primary outcome (safety) - OHSS per woman randomised Pituitary suppression methods In women with predicted normal response, short GnRH antagonist protocols may reduce OHSS compared with long GnRH agonist protocols (RR 0.88, 95% CI 0.78 to 0.99; 7 studies, 2650 women; I2 = 0%; low-certainty evidence). Short GnRH antagonist protocols In women with predicted high response receiving short GnRH antagonist protocols, hMG may reduce OHSS compared with rFSH (RR 0.45, 95% CI 0.3 to 0.68; 1 study, 619 women; low-certainty evidence). Secondary outcomes Clinical pregnancy Pituitary suppression methods In women with predicted normal response, network evidence suggested that ovarian stimulation without pituitary suppression lowers the clinical pregnancy rate compared with short GnRH antagonist protocols (RR 0.76, 95% CI 0.61 to 0.93; low-certainty evidence) and with GnRH agonist flare protocols (RR 0.60, 95% CI 0.44 to 0.82; low-certainty evidence). Cancellation Short GnRH antagonist protocols In women with predicted high response undergoing short GnRH antagonist protocols, hMG may increase cancellation compared with rFSH (RR 5.98, 95% CI 1.78 to 20.10; 1 study, 619 women; low-certainty evidence). For the remaining networks and participant subgroups (normal- and low-responding women), the evidence did not confidently identify differences between COS protocols and is not reported in the abstract. Oocyte number Pituitary suppression methods In women with predicted normal response, short GnRH antagonist protocols (MD -0.75, 95% CI -1.49 to -0.02; 17 studies, 4062 women; I2 = 94%; low-certainty evidence), GnRH agonist flare protocols (MD -3.30, 95% CI -4.87 to -1.73; 1 study, 240 women; I2 = 96%; low-certainty evidence) and protocols without pituitary suppression (MD -5.80, 95% CI -11.24 to -0.36; 2 studies, 714 women; low-certainty evidence) may lower the oocyte number compared with long GnRH agonist protocols, respectively. In women with predicted low response, short GnRH antagonist protocols may reduce the oocyte number versus long agonist protocols (MD -1.25, 95% CI -2.01 to -0.50; low-certainty evidence). Long GnRH agonist protocols In women with predicted normal response receiving long GnRH agonist protocols, combining rFSH and rLH reduces the oocyte number compared with rFSH alone (MD -0.81, 95% CI -1.33 to -0.28; 6 trials, 1289 women; I2 = 0%; high-certainty evidence). Remaining evidence For the remaining networks, patient subgroups and secondary outcomes, the evidence did not confidently identify differences between COS protocols. AUTHORS' CONCLUSIONS: Short GnRH antagonist protocols may reduce OHSS rates in women with predicted normal response without compromising LBR or OPR. Ovarian stimulation without pituitary suppression may reduce the LBR or OPR compared with short GnRH antagonist protocols and with GnRH agonist flare protocols. In women with predicted high response receiving short GnRH antagonist protocols, hMG may reduce OHSS compared with rFSH. We were unable to meta-analyse results from 169 trials due to serious risk of selection or other biases, a lack of outcome data, or because of data reported in an unsuitable format for meta-analysis (e.g. per cycle); this led to underpowered analyses for several outcomes and pairwise comparisons. Future trials should focus on evaluating the effect of different COS protocols upon cumulative live birth rates, accounting for all embryo transfers (fresh and/or frozen) after a single stimulation cycle per participant.
The Association Between Periconceptual Maternal Dietary Patterns and Miscarriage Risk in Women With Recurrent Miscarriages: A Multicentre Cohort Study.
OBJECTIVE: To examine the association between periconceptual maternal diet and miscarriage risk among women with recurrent miscarriages. DESIGN: Prospective multicentre cohort study (Tommy's Net). SETTING: Three university hospital research centres in the United Kingdom. POPULATION: 1035 women with a baseline history of two or more miscarriages. METHODS: We analysed baseline dietary data from a 10-item Food Frequency Questionnaire (FFQ). For individual food category analyses, we used multivariable Poisson regression following adjustment for maternal confounders and paternal dietary patterns. For whole diet analyses, ordinal principal component analysis (PCA) was used to identify common dietary patterns. Results were presented as relative risks (RR) with 95% confidence intervals (CI) and accompanying p-values. MAIN OUTCOME MEASURES: Miscarriage rate, defined as the rate of spontaneous pregnancy loss (
Reference charts for first-trimester placental volume derived using OxNNet.
OBJECTIVE: To establish a comprehensive reference range for OxNNet-derived first-trimester placental volume (FTPV), based on values observed in healthy pregnancies. METHODS: Data were obtained from the First Trimester Placental Ultrasound Study, an observational cohort study in which three-dimensional placental ultrasound imaging was performed between 11 + 2 and 14 + 1 weeks' gestation, alongside otherwise routine care. A subgroup of singleton pregnancies resulting in term live birth, without neonatal unit admission or major chromosomal or structural abnormality, were included. Exclusion criteria were fetal growth restriction, maternal diabetes mellitus, hypertensive disorders of pregnancy or other maternal medical conditions (e.g. chronic hypertension, antiphospholipid syndrome, systemic lupus erythematosus). Placental images were processed using the OxNNet toolkit, a software solution based on a fully convolutional neural network, for automated placental segmentation and volume calculation. Quantile regression and the lambda-mu-sigma (LMS) method were applied to model the distribution of FTPV, using both crown-rump length (CRL) and gestational age as predictors. Model fit was assessed using the Akaike information criterion (AIC), and centile curves were constructed for visual inspection. RESULTS: The cohort comprised 2547 cases. The distribution of FTPV across gestational ages was positively skewed, with variation in the distribution at different gestational timepoints. In model comparisons, the LMS method yielded lower AIC values compared with quantile regression models. For predicting FTPV from CRL, the LMS model with the Sinh-Arcsinh distribution achieved the best performance, with the lowest AIC value. For gestational-age-based prediction, the LMS model with the Box-Cox Cole and Green original distribution achieved the lowest AIC value. The LMS models were selected to construct centile charts for FTPV based on both CRL and gestational age. Evaluation of the centile charts revealed strong agreement between predicted and observed centiles, with minimal deviations. Both models demonstrated excellent calibration, and the Z-scores derived using each of the models confirmed normal distribution. CONCLUSIONS: This study established reference ranges for FTPV based on both CRL and gestational age in healthy pregnancies. The LMS method provided the best model fit, demonstrating excellent calibration and minimal deviations between predicted and observed centiles. These findings should facilitate the exploration of FTPV as a potential biomarker for adverse pregnancy outcome and provide a foundation for future research into its clinical applications. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
First-trimester biomarkers of gestational diabetes mellitus: A scoping review.
Gestational diabetes mellitus (GDM) affects approximately 14% of pregnancies globally, with rising incidence depending on the diagnostic criteria used. In the UK, screening relies on risk factors at booking, followed by a diagnosis via an oral glucose tolerance test in the second trimester. This approach may lack sensitivity and has poor tolerability. Emerging evidence suggests that GDM pathophysiology begins in the first trimester, with biomarkers showing potential for early prediction. Identifying these could enable earlier risk stratification, improved diagnostic pathways, and better maternal-fetal outcomes. This scoping review maps the existing literature on first-trimester biomarkers of GDM to evaluate their clinical utility and integration into predictive models. A literature search was conducted using Medline, Embase, and PubMed to identify studies on first-trimester biomarkers of GDM. Inclusion criteria included (1) studies investigating biomarkers at <15 weeks' gestation; (2) studies that diagnosed GDM using an OGTT with recognized diagnostic guidelines or clearly stated glucose thresholds. A total of 133 studies were included, reporting a wide range of biomarkers (145 in total). PAPP-A was generally lower in GDM, with mixed findings for β-hCG and PlGF. Metabolic markers, including lipid profiles, fasting glucose, and HbA1c, were often elevated. Inflammatory markers, such as WCC, neutrophils, and CRP, were higher in those later diagnosed with GDM. First-trimester biomarkers highlight GDM's complex pathophysiology. PAPP-A shows predictive potential, while metabolic and inflammatory biomarkers suggest early systemic dysfunction. Emerging tools like 3D ultrasonography indicate placental structural changes. Larger studies are needed to validate these biomarkers and integrate them into predictive models to improve maternal-fetal outcomes.
The Effect of Weight Loss Before In Vitro Fertilization on Reproductive Outcomes in Women With Obesity : A Systematic Review and Meta-analysis.
BACKGROUND: It is unclear whether weight loss before in vitro fertilization (IVF) improves reproductive outcomes in women with obesity. PURPOSE: To assess whether weight loss interventions before IVF improve reproductive outcomes. DATA SOURCES: Five electronic databases through 27 May 2025. STUDY SELECTION: Randomized controlled trials (RCTs) in women with obesity who were offered a weight loss intervention before planned IVF. DATA EXTRACTION: Dual independent screening, data extraction, and assessment of risk of bias (RoB) and certainty of evidence. Primary outcomes were pregnancy and live birth rates. Where appropriate, studies were pooled using random-effects meta-analyses. DATA SYNTHESIS: Twelve RCTs (1921 randomly assigned participants) were included, 7 of which had high RoB. There was moderate certainty that pre-IVF weight loss interventions were associated with an increase in total pregnancy rates (risk ratio [RR], 1.21 [95% CI, 1.02 to 1.44]; 11 studies) and pregnancies resulting from unassisted conception (RR, 1.47 [CI, 1.26 to 1.73]; 10 studies), whereas the effect on pregnancies resulting solely from IVF was uncertain. Weight loss interventions were not associated with pregnancy loss rates (RR, 1.05 [CI, 0.98 to 1.13]; 8 studies; moderate certainty), but their effect on live birth rates was unclear (RR, 1.15 [CI, 0.95 to 1.40]; 9 studies; very low certainty). LIMITATIONS: Studies were small, had high RoB, and often did not report important outcomes, such as live births. Substantial clinical and methodological heterogeneity was unexplained by exploratory analyses. CONCLUSION: Weight loss interventions before IVF appear to increase the chances of pregnancy, especially unassisted conceptions. However, studies were small, and heterogeneity made it difficult to determine the benefit of any particular intervention. PRIMARY FUNDING SOURCE: National Institute for Health and Care Research Applied Research Collaboration Oxford and Thames Valley. (PROSPERO: CRD42023441457).
First trimester maternal infections and offspring congenital heart defects: a meta-analysis.
BACKGROUND AND AIMS: Maternal infections have been proposed to play a role in the development of congenital heart defects (CHD). This study aims to synthesize contemporary evidence on the association between first-trimester maternal infection and risk of offspring CHD. METHODS: This systematic review and meta-analysis (PROSPERO number: CRD42024523638) used Embase, PubMed, Web of Science, Scopus, and the Cochrane Library to identify studies investigating first-trimester maternal infection and offspring CHD, published up until 30 September 2024. Human studies with a minimum of 50 cases were eligible. Inverse variance weighted random-effects models were conducted to pool estimates and stratify associations by infection type and heart defect type. RESULTS: A total of 30 studies (24 case-control, 3 cohort, and 3 cross-sectional studies) with 1 732 295 pregnancies were identified. Studies assessed maternal infectious status through self-reported questionnaires (n = 20, 66.7%), laboratory testing (n = 7, 23.3%) or medical records (n = 3, 10.0%). Overall, any first-trimester maternal infection was associated with higher risk of CHD in offspring, with a pooled odds ratio (OR) and 95% confidence interval (CI) of 1.63 (1.41, 1.88). Among specific types of infection, rubella virus, coxsackievirus, respiratory infections, and influenza presented higher risks of offspring CHD, with ORs (95% CI) of 2.78 (2.08, 3.72), 1.57 (1.12, 2.19), 1.57 (1.25, 1.96), and 1.50 (1.20, 1.87), respectively. Studies that reported associations by individual subtype of CHD relied on a comparatively modest number of cases. Pooled ORs for exposure to any first-trimester infection were 1.59 (1.16, 2.20) for ventricular septal defects, 1.55 (1.21, 1.99) for atrioventricular septal defects, and not statistically significant for other subtypes. CONCLUSIONS: First-trimester maternal infections are associated with increased risk of offspring CHD and appear to extend beyond infections commonly tested for during routine pregnancy screening. Larger-scale studies are warranted to confirm these findings using laboratory antibody testing and explore underlying mechanisms.
Subclinical Postpartum Renal Structure After Hypertensive Pregnancy Disorders.
BACKGROUND: Hypertensive pregnancies are associated with increased risks of renal failure in pregnancy and later life. However, traditional markers of renal function normalize postpartum, making identification of those at future disease risk difficult. We studied whether the type and severity of hypertensive pregnancy associated with postpartum renal structure. METHODS: One hundred twenty-five women from interventional trials (61 preeclamptic, 33 gestational hypertension, and 31 normotensive pregnancy), aged ≥18 years, were imaged using magnetic resonance imaging 6 to 12 months postpartum. Anthropometric, demographic, blood pressure, and blood sample data were collected during pregnancy and postpartum. Kidney volume indexed to body surface area and corticomedullary differentiation were compared between groups using a 1-way ANCOVA, whereas associations with other outcomes were assessed using correlation tests. RESULTS: Postpartum total kidney volume indexed to body surface area was smaller in women who had preeclampsia compared with those who had gestational hypertension or a normotensive pregnancy (P=0.049). Total kidney volume postpartum correlated with estimated glomerular filtration rate at delivery (P<0.001). However, smaller volumes were not explained by reduced corticomedullary differentiation, which only differed in women with gestational hypertension compared with preeclamptic (P=0.02) and normotensive women (P=0.007). There were no associations between renal measures and blood pressure during or after pregnancy. CONCLUSIONS: At 6 to 12 months postpartum, preeclamptic women have smaller kidney volumes than women with gestational hypertension or normotensive pregnancies. These smaller volumes relate to lower renal function at delivery but not corticomedullary differentiation, which only differed in women with gestational hypertension. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT04273854 and NCT05434195.
The range and reach of qualitative research in neurosurgery: A scoping review.
Following calls for more qualitative research in neurosurgery, this scoping review aimed to describe the range and reach of qualitative studies relevant to the field of neurosurgery and the patients and families affected by neurosurgical conditions. A systematic search was conducted in September 2024 across six databases: Medline via Ebsco; Embase via OVID; PsycINFO via Ebsco; Scopus; Web of Science Core Collection; and Global Health via Ebsco. Eligibility criteria were based on Population, Concept, and Context. The search identified 18,809 hits for screening with 812 included in the final analysis. Seven themes were identified from a content analysis of study aims: 1 Perspectives of living with a neurosurgical condition; 2 Family perspectives; 3 Perceptions of neurosurgery; 4 Perceptions of general healthcare care; 5 Decision making; 6 Advancing neurosurgery; and, 7 Understanding neurosurgical conditions. Traumatology was identified as the most researched sub-specialty (43.2%) yet few studies were led explicitly by a neurosurgeon (1.6%) or those with a neurosurgical affiliation (10.5%). Lead authors were predominantly from high income countries (93.7%), as were most multi-author teams (86.6%). There was a trend towards increasing publication over time; however, only 8.4% of papers were published in neurosurgical specific journals. The data set had an average Field Weighted Citation Impact of 0.96 and Field Weighted Views Impact of 1.11, 18.9% were cited in policy documents in 15 countries. This scoping review provides a comprehensive picture of the current qualitative research base in neurosurgery and suggests ways to improve the conduct and reporting of such studies in the future. Addressing these challenges is crucial if qualitative research is to advance the neurosurgical evidence base in a rigorous way.
Women in science: bridging gaps in basic sciences.
The Supporting Women in Science (SWIS) program aims to strengthen female representation in research in developing countries. This article highlights the program participation, mentorship challenges, and systemic barriers. Findings inform inclusive, discipline-specific strategies designed to support women's research capacity, academic leadership, and advancement in the global scientific community.
Systematic review and meta-analysis of the importance of pre-pregnancy maternal health on the risk of hypertensive disorders of pregnancy.
Stratifying women using their medical history pre-pregnancy may allow early identification of women at high-risk of Hypertensive disorders of pregnancy (HDP), a common and high-burden obstetrical complication. This would allow the establishment of early preventative approaches, however, most research into pregestational conditions comes from data taken during pregnancy. To address this gap, we conducted a systematic review with meta-analysis, adhering to PRISMA and MOOSE guidelines. Our review comprehensively examined the impact of a broad range of medical disorders exclusively diagnosed pre-pregnancy on the development of HDP, including preeclampsia, gestational hypertension, superimposed preeclampsia, eclampsia and HELLP. We searched Medline (OvidSP) and Embase (OvidSP) databases from inception to 8th May 2021 and calculated relative risks ratios, adjusted for study quality, or percentage incidences. 406/8724 studies were included for qualitative research, 177 of which classified for quantitative assessment. HDP risk increased with pregestational renal conditions (7.76, CI: 5.62-10.71), hypertension (3.68, CI: 1.51-8.97), diabetes (3.57, CI: 2.71-4.70), and high body mass index (2.65, CI: 2.33-3.03); as well as with pregestational polycystic ovarian syndrome (1.90, CI: 1.46-2.48), rheumatoid arthritis (1.54, CI: 1.42-1.67), migraines (1.53, CI: 1.32-1.78), and anxiety/depression (1.52, CI: 1.16-2.00). Pregestational antiphospholipid syndrome, systemic lupus erythematosus, and Takayasu arteritis also increased the incidence of gestational hypertension (8 %, 7 %, 17 %) and preeclampsia (37 %, 17 %, 23 %). Overall, this review shows pre-pregnancy maternal health can help stratify HDP risk, and highlights the importance of often-overlooked risk factors in current national guidelines and assessment tools. Crucially, we provide an evidence-based graphical abstract/list of the identified pregestational risk factors as reference for medical practitioners providing pre-pregnancy counselling.